Desmosomes are prominent cell-cell junctions in stratified squamous epithelial tissues, whose composition varies among cells of the different layers of the tissue. It is not known why cells utilize different components to assemble desmosomes within the same tissue. However, it is likely that desmosomes comprised of different molecular components perform diverse functions and lead to altered adhesive characteristics. Desmosomal protein expression is generally reduced in squamous cell carcinomas; however, the contribution of these proteins to tumorigenesis is largely unknown. Our long-term goals are to understand the role desmosomes play in maintaining the normal phenotype of squamous epithelial tissues and to determine if their alteration during tumorigenesis influences cellular behavior. Our hypothesis is that changes in desmosomal composition result in differential adhesion and/or altered cell-cell signaling. Our laboratory has extensive experience in functional analysis of cell-cell adhesion and cell motility, and we are positioned to make significant contributions to our understanding of desmosome function and the role this cellular structure plays in the development of squamous cell carcinomas. The specific aims are: 1) To determine if the composition of desmosomes influences cell adhesion, proliferation and motility; and 2) To further understand the function of plakophilin-1 in the desmosome and in the nucleus. Plakophilin-1 is a desmosomal protein that is found in the nucleus as well as in the plasma membrane, which led us to propose that plakophilin-1 participates in nuclear signaling that may be linked to desmosomal adhesion. We will use structure/function studies to investigate the mechanism of nucleo-cytoplasmic transport of plakophilin-1 ; use a unique "activatible" form of plakophilin-1 to investigate the role of this protein in adhesion and in cellular signaling; and investigate nuclear proteins that associate with plakophilin-1. Collectively, the studies proposed herein will define the contribution of desmosomal components to cellular motility, invasiveness and signaling.